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Drug Metabolism and Disposition Fast Forward
First published on July 28, 2005; DOI: 10.1124/dmd.105.005892

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Received for publication June 2, 2005.
Revised July 26, 2005.
Accepted for publication July 27, 2005.

Extracts and kavalactones of Piper methysticum G. FORST (kava-kava) inhibit P-glycoprotein in vitro

Johanna Weiss 1*, Alexandra Sauer 1, Andreas Frank 2, Matthias Unger 2

1 University Hospital Heidelberg 2 University of Wurzburg

* Address correspondence to: E-mail: johanna_weiss{at}med.uni-heidelberg.de

Abstract

Root extracts from kava-kava (Piper methysticum G. FORST) are clinically used for the treatment of anxiety and restlessness. Due to reported cases of liver toxicity, kava-kava extracts were withdrawn from the market in several countries in 2002. Because the efflux transporter P-glycoprotein (P-gp) is involved in the absorption, distribution and excretion of many drugs and often participates in drug-drug interactions, we studied the effect of a crude kava extract and the main kavalactones kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin on the P-gp-mediated efflux of calcein-AM in the P-gp over-expressing cell line P388/dx and the corresponding cell line P388. The crude extract and the kavalactones showed a moderate to potent inhibitory activity with f2 (concentration needed to double baseline fluorescence) values of 170 µg/ml and 17-90 µM, respectively. The f2 value of yangonin could not be determined due to its higher lipophilicity. In conclusion, our results for the first time demonstrate P-gp inhibitory activity of kava-kava and its components in vitro.


Key words: ABC transporters, absorption, adverse drug reactions, clinical pharmacology, drug-drug interactions, p-glycoprotein


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